Activation of protein kinase A and atypical protein kinase C by A(2A) adenosine receptors antagonizes apoptosis due to serum deprivation in PC12 cells

• Published in: The Journal of biological chemistry Vol. 276; no. 17; p. 13838
• Main Authors: Huang, N K, Lin, Y W, Huang, C L, Messing, R O, Chern, Y
• Format: Journal Article
• Language: English
• Published: United States 27.04.2001
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Animals; Apoptosis; Blotting, Western; Cell Membrane - metabolism; Cell Nucleus - metabolism; Cell Survival; Chromones - pharmacology; Colforsin - pharmacology; Coloring Agents - pharmacology; Culture Media, Serum-Free - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Cytosol - metabolism; DNA Fragmentation; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Activation; Enzyme Inhibitors - pharmacology; Flow Cytometry; Genes, Dominant; MAP Kinase Signaling System; Models, Biological; Morpholines - pharmacology; PC12 Cells; Phenethylamines - pharmacology; Phosphoinositide-3 Kinase Inhibitors; Phosphoprotein Phosphatases - metabolism; Protein Kinase C - metabolism; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-akt; Rats; Receptor, Adenosine A2A; Receptors, Purinergic P1 - metabolism; Signal Transduction; Tetrazolium Salts - pharmacology; Thiazoles - pharmacology; Time Factors; Transfection
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M008589200

We found in the present study that stimulation of A(2A) adenosine receptors (A(2A)-R) prevents apoptosis in PC12 cells. This A(2A)-protective effect was blocked by protein kinase A (PKA) inhibitors and was not observed in a PKA-deficient PC12 variant. Stimulation of PKA also prevented apoptosis, suggesting that PKA is required for the protective effect of A(2A)-R. A general PKC inhibitor, but not down-regulation of conventional and novel PKCs, readily blocked the protective effect of A(2A)-R stimulation and PKA activation, suggesting that atypical PKCs (aPKCs) serve a critical role downstream of PKA. Consistent with this hypothesis, stimulation of A(2A)-R or PKA enhanced nuclear aPKC activity. In addition, the A(2A)-protective effect was blocked by a specific inhibitor of one aPKC, PKCzeta, whereas overexpression of a dominant-positive PKCzeta enhanced survival. In contrast, inhibitors of MAP kinase and phosphatidylinositol 3-kinase did not modulate the A(2A)-protective effect. Dominant-negative Akt also did not alter the A(2A)-protective effect, whereas it significantly reduced the protective action of nerve growth factor. Collectively, these data suggest that aPKCs can function downstream of PKA to mediate the A(2A)-R-promoted survival of PC12 cells. Furthermore, the results indicate that different extracellular stimuli can employ distinct signaling pathways to protect against apoptosis induced by the same insult.